The field of the invention relates to small molecular inhibitors of enzymes involved in autophagy. In particular, the field of the invention relates to small molecular inhibitors of ubiquitin-like modifier-activing enzyme ATG7 which are analogs of adenosine monophosphate (AMP).
Rapidly proliferating cancer cells need free amino acid building blocks to meet their metabolic needs and to maintain proper organelle quality control. Autophagy or the process of “self eating” plays an essential role to supply the intracellular pool of amino acids by degrading intracellular organelles/proteins as well as proteins scavenged from the extracellular space. Therefore, inhibition of autophagy is promising strategy to treat cancers, because autophagy inhibitors will reduce the internal supply of free amino acids for cancer cells, resulting in the inhibition of cancer cell growth.
In addition, autophagy inhibitors can lead to accumulation of defective mitochondria leading to the increase in reactive oxygen species in cancer cells, which leads to inhibition of cell proliferation, and conversion of malignant cancer cells into benign tumors called oncocytomas. This conversion to oncocytomas occurs because defective mitochondria are removed via the autophagy pathway, and if autophagy is inhibited then defective mitochondria accumulate. In addition, in some types of cancers autophagy is involved in clearing misfolded proteins to alleviate endoplasmic reticulum (ER) stress. In such cases inhibition of autophagy leads to accumulation of misfolded proteins in the ER, ER stress and apoptosis. In recent years, emerging evidence shows that autophagy is particularly important for the survival of K-Ras driven pancreatic and lung cancers, and B-Raf (V600E) driven melanomas and lung cancers, as well as PTEN deficient prostate cancers. This opens the path for using autophagy inhibitors in personalized therapy; i.e. for example if the tumor in patient is driven by K-Ras or B-Raf V600E mutation or PTEN deficiency than a decision could be made to administer autophagy inhibitors as therapeutics for such tumors (see: Genes & Dev. 2016. 30: 399-407; Cancer Discov. 2015 April; 5(4):410-23; Genes & Dev. 2013. 27: 1447-1461; Cancer Discov. 2013 November; 3(11):1272-85; Nature, 2015, 524, 361-365).
In particular, ubiquitin-like modifier-activing enzyme ATG7 presents a potential target for autophagy inhibitors. Ubiquitin-like modifier-activing enzyme ATG7 is an essential enzyme which is important for autophagy activation, and inhibition of ATG7 using gene knock-out techniques in vivo has been shown to inhibit the growth of K-Ras driven pancreatic and lung cancers, V600E B-Raf melanoma and lung cancers, and PTEN deficient prostate cancers (Genes & Dev. 2016. 30: 399-407; Cancer Discov. 2015 April; 5(4):410-23; Cancer Discov. 2013 November; 3(11):1272-85; Nature, 2015, 524, 361-365; Nature. 2013 Dec. 12; 504(7479):296-300; Autophagy. 2014 February; 10(2):384-5; Genes Dev. 2013 Jul. 1; 27(13):1447-61). Therefore, ATG7 is a potential drug target to treat these devastating diseases. In the present disclosure, we propose the development of first in class ATG7 covalent inhibitors using a novel inhibitor design concept that exploits the conformational flexibility of ATG7 enzyme in binding to adenosine monophosphate (AMP). The disclosed AMP analog inhibitors of ATG7 have the potential to become anticancer drugs.